Hyperbranched vs Linear Poly(β-amino ester)s: Polymer Topology and End-Group Hydrophilicity Govern Degradation Kinetics, Transfection Efficiency, and Biocompatibility

Poly(β-amino ester)s (PBAEs) are widely employed as nonviral vectors due to their facile synthesis, biodegradability, and strong transfection performance. However, their degradation behaviors and delivery efficiencies vary substantially with structural features. This study compared hyperbranched and linear PBAEs with different end-capping groups to investigate how polymer structure influences biodegradation and gene delivery. Experimental results indicated that hyperbranched PBAEs (HPAEs) exhibited slower degradation kinetics than their linear analogues (LPAEs). HPAE/DNA nanoparticles maintained stronger DNA retention and achieved higher initial transfection, whereas the more rapidly degrading LPAEs released DNA earlier, resulting in a sustained yet lower expression profile. All PBAEs underwent complete degradation within 24 h. Both architectures were noncytotoxic in vitro, and HPAEs further exhibited negligible systemic toxicity in vivo, confirming their favorable biocompatibility. Together, these findings delineate a clearer relationship between polymer structure, stability, and delivery efficiency in HPAE/LPAE systems, thereby informing the design of next-generation PBAE vectors.